Although mature plasma cells constitute the vast majority of tumor cells and are responsible for clinical symptoms in multiple myeloma (MM), they have little to no clonogenic growth potential either in vitro or in vivo. We have recently found that clonotypic MM cells phenotypically resembling normal memory B cells are able to give rise to mature plasma cells in immunodeficient mice and propagate disease during serial transplantation. These results demonstrate that these cells are capable of both differentiation and self-renewal, suggesting that they represent the cancer stem cell (CSC) in MM. We have recently found that MM CSCs are resistant to standard chemotherapeutic agents, but can be targeted by the Hedgehog (Hh) signaling pathway that is active during normal embryonic development and in a wide variety of cancers. Several novel Hh pathway inhibitors have recently entered clinical testing, and one of these has exhibited clinical activity validating Hh signaling as a therapeutic target in human cancers. However, all of these approaches have been designed to inhibit SMOOTHEDED (SMO) a key component of the Hh signal transduction pathway, and emergence of resistance mechanisms have been reported. Therefore, novel strategies capable of inhibiting Hh signaling without directly targeting SMO are needed. Our preliminary data demonstrate that agonists of the Liver X Receptor (LXR), a nuclear hormone receptor that interacts with Hh signaling in normal cells, can attenuate Hh pathway activity in MM, reduce the frequency of MM CSC, and limit clonogenic MM growth in vitro. Therefore, we hypothesize that LXR agonists are novel anti-cancer agents that may target MM CSCs through the inhibition of Hh signaling. We propose to build on these findings and will specifically: 1). Examine the effects of LXR agonists in MM and 2). Examine the interaction between the LXR and Hedgehog signaling pathways in MM. PUBLIC HEALTH RELEVANCE: Multiple myeloma is largely an incurable disease, but we recently identified myeloma stem cells that may be responsible for disease relapse and progression. We will study whether a novel pathway regulated by the Liver X receptor can inhibit myeloma stem cells and improve clinical outcomes.